Process for producing quinoxaline-di-N-oxides

ABSTRACT

The novel process for the preparation of methyl 3-(2quinoxalinylmethylene)carbazate N1, N4-dioxide which comprises contacting methyl 3-(2-quinoxalinylmethylene)carbazate with oxidizing agent in reaction-inert solvent at a temperature of from about 20*C. up to 100*C. until reaction is substantially complete, said oxidizing agent being selected from the group consisting of peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, perphthalic acid, performic acid, trifluoroperacetic acid and hydrogen peroxide.

United States Patent [191 Kuhla 5] Dec. 16, 1975 PROCESS FOR PRODUCING3,720,673 3/1973 Bowie 260/250 QN QUINOXALINEDLNOXIDES 3,819,616 6/1974Seng et at, 260/250 0 [75] Inventor: Donald E. Kuhla, Gales Ferry,

Conn.

[73] Assignee: Pfizer Inc., New York, NY.

[22] Filed: Mar. 7, 1973 [21] Appl. No.: 338,906

[52] US. Cl 260/250 Q; 424/250 [51] Int. Cl. C07D 241/36 [58] Field ofSearch 260/250 Q, 250 ON [56] References Cited UNITED STATES PATENTS2,545,786 3/l95l Landquist 260/250 QN 2,626,259 4/l974 Landquist 260/250QN Primary ExaminerRichard J Gallagher Assistant ExaminerDavid E,Wheeler Attorney, Agent, or Firm-Connolly and Hutz 57 ABSTRACT The novelprocess for the preparation of methyl 3-(2-quinoxalinylmethylene)carbazate N, N -dioxide which comprises contactingmethyl 3-(2- quinoxalinylmethylene)carbazate with oxidizing agent inreaction-inert solvent at a temperature of from about 20C. up to 100C.until reaction is substantially complete, said oxidizing agent beingselected from the group consisting of peracetic acid, perbenzoic acid,m-chloroperbenzoic acid, perphthalic acid, performic acid,trifluoroperacetic acid and hydrogen peroxide.

2 Claims, No Drawings PROCESS FOR PRODUCING Umox LmE-m-N-oxmizs,BACKGROQ DQF THE INVENTION mals. (Australian Vet. 1.48,,No. 579, (1972)21I1d Rec. Med. Vet. ecole Alfort. 148 No. 3 365-73 (1972)). l

SUMMARY OF THE INVENTION Accordingly the present invention discloses aprocess for the preparation of methyl 3-(2-quinoxalinylmethylene)carbazate N ,N -dioxide which comprisescontacting methyl 3-(2-quinoxalinylmethylene)carbazate with at leastabout 2 equivalents of oxidizing agent in a reaction inert solvent at atemperature of from about C. up to 100C. until the reaction issubstantially complete, said oxidizing agent being selected from thegroup consisting of peracetic acid, perbenzoic acid, mchloroperbenzoicacid, perphthalic acid, performic acid, trifluoroperacetic acid andhydrogen peroxide, and recovery of the product. In the case of hydrogenperoxide a catalyst is usually employed. Suitable catalysts are tungsticacid, sodium tungstate, sodium vanadate, sodium molybdate, potassiumtungstate, potassium molybdate, vanadium pentaoxide, zirconium dioxide,tungsten trioxide or molybdenum trioxide.

A particularly preferred embodiment of the herein described inventionconcerns the above process wherein said oxidizing agent is peraceticacid and said solvent is acetic acid, since both the reagent and solventare inexpensive.

A second preferred embodiment of the herein described invention concernsthe above process wherein said oxidizing agent is m-chloroperbenzoicacid and said solvent is chloroform. P

In both of the above embodiments the reaction tem perature is preferablymaintained at less than 50C.

The new reaction of the present invention is carried out in areaction-inert solvent. An inert solvent for purposes of this inventioncontemplates any solvent which allows solubilization of the reactantsand is free of ad.- verse effect on the reagents and products under theconditions employed. Two preferred types include organic acids, such asacetic acid, and halogenated solvents, such as chloroform and methylenechloride. In some cases water may be employed. However, any solventpossessing the qualities set forth above will be satisfactory. Thetemperature at which the reaction is performed may vary from C. to about100C. and for the most part the optimum temperature will vary with thechoice of oxidizing agent. Depending upon the particular oxidizing agentand temperature, the reaction time can vary from a few minutes to aslong as 24 hours. Generally, to ensure complete reaction the relativelylong time periods are preferred. Optimum reaction conditions are readilydetermined by experiment.

The proportion of oxidizing agent relative to the starting carbazate mayvary widely butfor efficient conversion at least about two equivalentsof oxidizing agent per mole ofcar bazate are preferred.

The product is a crystalline substance which precipitates from thereaction mixture. It is collected by suit- .able means and dried. F

- The valuable product of this invention exhibits activity as urinarytract systemic anti-infective in animals, includingman, against a wide:variety of microorganisms including Gram positive and Gram-negativebacteria. It is especially valuable against Gram negative infection bothinvitro and in vivo.

Further, the addition of a low level of the herein described Schiff baseto the diet of animals, both ruminant and non-ruminant, such that theseanimals receive the product over an extended period of time, at a levelof from about 0.04 mg./kg. to about 10 mg./kg. of body weight per day,especially over a major portion of their active growth period, resultsin an acceleration of the rate of growth and improved feed efficiency.Included in these two classes of animals are poultry (chickens, ducks,turkeys), cattle, sheep, dogs, cats, swine, rats, mice, horses, goats,mules, rabbits, mink, etc. The beneficial effects in growth rate andfeed efficiency are over and above what is normally obtained withcomplete nutritious diets containing all the nutrients, vitamins,minerals and other factors known to be required for the maximum healthygrowth of such animals. The animals thus attain market size sooner andon less feed.

These feed compositions have been found to be particularly valuable andoutstanding in the case of such animals as poultry, rats, hogs, swine,lambs, cattle, and the like. In some instances the degree of responsemay vary with respect to the sex of the animals. The products, may, ofcourse, be administered in one component of the feed or they may beblended uniformly throughout a mixed feed; alternatively as noted above,they may be administered in an equivalent amount via the animalss waterration. It should be noted that a variety of feed components may be ofuse in the nutritionally balanced feeds.

PREPARATION I A solution of 14.0 g (0.0886 mole) of2-quinoxalinecarboxaldehyde (prepared by the method of Landquist andSilk, J. Chem. Soc. 1956, 2052), 100 ml of ethanol and 14.0 g (0.156mole) of methylcarbazate is heated to reflux on a steam bath and is thenallowed to stand at room temperature overnight/The product, methyl3-(2-quinoxalinylmethylene)carbazate, crystallizes: yield 14.0 g (69percent); m.p. 242244.

EXAMPLE I To a solution of methyl 3-(2-quinoxalinylmethylene)carbazate(46 g, 0.20 mole) in glacial acetic acid (200 ml) is added, in adropwise manner, 40 percent peracetic acid (76 g, 0.40 mole) with therate of addition such to maintain the temperature below about 50C.

The reaction mixture is allowed to stand for 12 hours and then dilutedwith water. The solid which precipitates is collected, washed with waterand dried to give crystalline methyl3-(2-quinoxalinylmethylene)carbazate N ,N -dioxide.

EXAMPLE II To a solution of methyl 3-(2-quinoxalinylmethylene)carbazate(46 g, 0.20 mole) in chloroform (300 ml) is added a solution of percentm- 3 chloroperbenzoic acid (82 g, 0.40 mole) in chloroform (300 ml). Thereaction temperature is maintained below 50C. by adjusting the rate ofaddition and using external cooling.

After stirring 24 hours, the mixture is filtered and the solid slurriedwith excess aqueous sodium bicarbonate to remove m-chlorobenzoic acid.The slurry is filtered and the solid washed with water and dried to givemethyl 3-(2-quinoxalinylmethylene)carbazate N,N- dioxide as acrystalline solid.

EXAMPLE lll A mixture of methyl 3-( 2-quinoxalinylmethylene)- carbazate(23.0 g, 0.1 mole), tungstic acid (2.5 g) and 30 ml of t-butanol isheated to 6065. An aqueous solution of 30 percent hydrogen peroxide (30ml) is solvent is acetic acid.

1. A PROCESS FOR THE PREPARATION OFMETHYL-3-(2-QUINOXALINYLMETHYLENE)CARBAZATE-N1,N4-DIOXIDE WHICHCOMPRISES THE STEP OF REACTING METHYL-3-(2-QUINOXALINYLMETHYLENE)CARBAZATE WITH ABOUT TWO EQUIVALENTS OF PERACETIC ACID IN AREACTION INERT SOLVENT AT A TEMPERATURE OF FROM ABOUT 20* UP TO 100*C.UNTIL REACTION IS SUBSTANTIALLY COMPLETE.
 2. The process of claim 1wherein said reaction inert solvent is acetic acid.